The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Several virus infections are major global public health problems. Some viruses cause chronic infections and carriers of untreated chronic infections are at increased risk of developing long-term complications, such as hepatic failure or cancer. It has been estimated that every year more than 1 million chronic Hepatitis B virus (HBV) infection patients die from the liver complications caused by the infection. Interferons and antiviral nucleoside and nucleotide analogues are used to cure or to suppress the replication activities of virus to keep the infection inactive and to prevent the progression of complications. The most common treatment options include daily oral self-administration or daily injections (or several weekly injections). Due to the long-term or even life-long drug therapy, daily self-administration requires strong commitment from the patient. This is also a challenge from the viewpoint of patient compliance as any longer treatment break promote antiviral drug resistance and recurrence is likely to occur when the suppressive effect of antivirals is omitted. Hence, there is an unmet need for long-term depot formulations in the treatment of virus infections and especially for minimally invasive ones, such as injectable formulations with relatively long administration intervals.
Silica gels have widely been used as a carrier material for controlled drug delivery and they can be processed into different dosage forms and the dosage forms can be combined to result in silica-silica composites with specific properties. Sol-gel derived silica microparticles with encapsulated drugs can be combined with a silica sol to form an injectable hydrogel depot composite for controlled delivery of antiviral drugs.
WO 2014/207304 by Jokinen et al, discloses shear-thinning combined hydrogel compositions formed from spray-dried silica microparticles with encapsulated agents and silica sols.
KR20120138908 discloses entecavir-containing microspheres and process for preparing the same.
WO2015020240 discloses entecavir microspheres and pharmaceutical composition for parenteral administration containing same.
Recently, a pegylated alpha-interferon was developed and, launched by Genentech/Roche for once-a-week injection treatment of chronic HBV infection. However, interferon therapy is associated with frequent systemic side effects, and it cannot be administered to patients with decompensated liver function.